1. Field of the Invention
Unrelated to their function of binding to H1 histamine receptors, the first-generation antihistamines produce sedation, an unwanted side effect, but also provide anticholinergic effects, which are helpful for reducing secretions and controlling rhinorrhea. Second-generation antihistamines, which are relatively nonsedating, have been developed but are lacking in anticholinergic efficacy. Despite the abundance of presently marketed formulations for addressing the symptoms for allergic rhinitis, no medicinal formulation is presently available which provides both antihistaminic and anticholinergic actions in an essentially nonsedating manner.
2. The State of the Art
Allergic rhinitis refers to a common inflammatory condition of the nose caused by allergies and affects at least 15% of the United States population. The typical symptoms of allergic rhinitis include: sneezing, itching nose, nasal congestion and rhinorrhea ("running" or "runny" nose), often accompanied by watering and itching eyes, and post nasal drip. As related to a patient's quality of life, rhinorrhea is reported as the most prominent and distressing symptom of allergic rhinitis.
The release of histamine is an important mechanism underlying some of the symptoms of allergic rhinitis. The symptom of rhinorrhea, however, is largely attributable to a neuronal mechanism; specifically, to the effects of acetylcholine on nasal cholinergic receptors, rather than to the action of histamine. This can be demonstrated by observing that histamine challenge on one side of the nose produces an increase in nasal secretions, on the other side as well. The reflex increase in secretions on the non-challenged side can be inhibited by premedication with an anticholinergic agent, i.e., an agent which acts to blocks the action of acetylcholine on cholinergic receptors.
Two categories of medication used to treat allergic rhinitis are capable of blocking the action of acetylcholine on cholinergic neuronal receptors: (i) first-generation antihistamines, which typically inherently have anticholinergic effects, and (ii) specific anticholinergic agents.
Antihistamines of the type which antagonize H1-histamine receptors are the most frequently used medications to treat allergic rhinitis. Histamine is an important mediator released in allergic reactions, and the primary action of antihistamines relates to their ability to bind competitively to H1-histamine receptors on target organ sites, thereby blocking the ability of histamine to bind to these receptors. The first pharmaceutical entities recognized to have this property, now referred to as first-generation antihistamines, have lipophilic chemical properties, which contribute to both their sedating and their anticholinergic effects. Examples of such sedating antihistamines area brompheniramine, chlorpheniramine, diphenhydramine, promethazine, and hydroxyzine.
The sedating side effects of antihistamines have stimulated the development and marketing of non-sedating, or second-generation, antihistamines. All are less lipophilic than first-generation antihistamines, conferring a reduction in their ability to cross the blood-brain barrier and thereby cause sedation. However, these second-generation antihistamines have a concomitant diminution of anticholinergic effects and decreased potency for controlling rhinorrhea. Examples of second-generation antihistamines are: loratidine (marketed as Claritin.RTM.), fexofenadine (marketed as Allegra.RTM.), cetirizine (marketed as Zyrtec.RTM.), and astemizole (marketed as Hismanal.RTM.).
Anticholinergic agents are exemplified by the belladonna alkaloids atropine and scopolamine, which inhibit the muscarinic action of acetylcholine on structures innervated by postganglionic cholinergic nerves. These agents typically inhibit the nasal secretory mechanism and cause drying of the nasal membranes. Anticholinergic agents also are known to exert central effects which include papillary dilatation and stimulation and depression of the CNS. Attention to the central effects of the anticholinergic agent considered and the relationship of the amount of dosage to central effects are of importance in devising a non-sedating oral dosage unit for rhinitis. Drowsiness is known to occur with high doses of anticholinergic agents, and with therapeutic doses of oral scopolamine, but drowsiness is considered rare with therapeutic doses of other oral anticholinergic agents (USPDI Drug Information for the Health Care Professional, 16th Edition, United States Pharmacopoeia Convention, Inc., 219-235, 1996 Rand McNally, Taunton, Mass.). Further, anticholinergic pharmaceuticals have been developed which have a limited capacity to pass across lipid membranes, such as the blood-brain barrier, and therefore have a limited capacity to produce central effects. Examples of these agents are the quaternary ammonium compounds methscopolamine and glycopyrrolate.
A multitude of medications are presently marketed and indicated for treating the symptoms of allergic rhinitis. None however, provides antihistaminic activity, anticholinergic activity, and a low potential for sedation. Some of the presently marketed formulations do contain both an antihistamine and an anticholinergic agent, but all are sedating by virtue of including a sedating antihistamine, and some are sedating because of the sedating anticholinergic agent scopolamine. Examples of these are:
1. Dura-vent DAS Tablets, which contains: phenylepherine 30 mg; chlorpheniramine 8 mg; and methscopolamine nitrate 3.5 mg. The first-generation antihistamine, chlorpheniramine, is sedating.
2. Atrohist.RTM. Plus, which contains: phenylepherine hydrochloride 25 mg, phenylepherine 50 mg, chlorpheniramine 8 mg, and hyoscyamine sulfate 0.19 mg; atropine sulfate 0.04 mg, and scopolamine hydrobromide 0.01 mg, and has the potential for sedation by virtue of the incorporation of the sedating antihistamine, chlorpheniramine, and the sedating anticholinergic agent scopolamine.
No oral medicinal formulation is presently available to a user which provides both antihistaminic and anticholinergic actions in a manner unlikely to produce sedation, despite the prevalence of allergic rhinitis and patients seeking attention for its treatment.